Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are important causes of chronic liver disease in the United States. The NASH Clinical Research Network (NASH CRN) was established in 2002 to conduct research related to its clinical features, risk factors, pathogenesis, natural history and treatment in children and adults. The initial funding period of the NASH CRN has been very productive in establishing and conducting network-wide protocols and numerous ancillary and pilot studies. Encouraged by its success, the NIDDK has issued RFA-DK-08-505 whose objective is to continue the NASH CRN for additional five years. The objectives of the NASH CRN during the next funding period are (a) to successfully complete three network-vde studies initiated during the initial funding period. They are an observational longitudinal study of NAFLD in adults and children (NAFLD Database study, n=l,215), a randomized double blind controlled therapeutic study of NASH in non-diabetic adults (PIVENS, n=247), and a randomized double blind controlled therapeutic study of NAFLD in children (TONIC, n=173). The NAFLD Database study may be amended to meet additional goals during the next funding period. These modifications may include extending the length of follow-up of those enrolled, consideration of a follow-up liver biopsy In a subset of patients without cirrhosis for better assessment of histological natural history and enrolling carefully chosen controls without NAFLD (b) to successfully complete a large of ancillary studies and pilot studies that have been begun during the Initial funding period, (c) to conduct additional therapeutic studies in adults and children with NASH as options currently available to treat NASH are quite limited. Subsets of patients requiring immediate attention include (but not limited) to those with diabetes or cirrhosis and (d) to initiate and complete additional ancillary studies based on extensive clinical material and biosamples collected thus far. These studies may focus on (but not limited to) natural history of NAFLD and NASH In children and adults, non-invasive assessment of disease severity (e.g., proteomics, llpodimics, clinical prediction rules) and disease pathogenesis (cytokine analyses, genome-wide association studies, tissue proteomics). Public Health Relevance: (provided by the applicant): NAFLD and NASH are important health problems and their incidence is expected to increase. During the initial funding period, the CRN has made important contributions to the field of NAFLD and NASH, however there remain numerous unanswered questions. During the next funding period, the CRN will continue to investigate risk factors, clinical aspects, natural history and optimal treatment for NASH and associated conditions